The candidate Tanya Froehlich, MD is a board-certified Developmental and Behavioral Pediatrician who completed an NRSA research fellowship and an MS in Epidemiology. Her career goal is to become an independent investigator focused on improving treatment delivery and outcomes for children with ADHD. The project Mentor Jeff Epstein, PhD is an established investigator with nationally;recognized expertise in ADHD treatment outcomes research. Dr. Froehlich has assembled an outstanding mentorship team, including NIH- funded investigators with expertise in ADHD treatment and pharmacogentics . Her research environment - Cincinnati Children's Hospital - is exceptional, and includes a dedicated clinical and research Center for ADHD as well as the only Genetic Pharmacology Program at a U.S. pediatric hospital. Proposed Research: Robust data show that stimulant medications reduce ADHD symptoms and impairment, but it is unclear whether their efficacy differs across the ADHD subtypes. Predominantly inattentive type (PIT) is the most prevalent ADHD subtype in U.S. population-based studies, but few studies have examined stimulant response in this subtype. Instead, PIT medication guidelines have largely been extrapolated from studies enrolling all or mostly ADHD-combined type (CT). Thus, this proposal seeks to further understanding of stimulant response and its predictors in children with PIT. We will evaluate participants'response to methylphenidate (MPH), the most widely prescribed stimulant, via a prospective, double-blind, placebo- controlled crossover trial with 3 dose conditions. Our first specific aim is to examine MPH medication and dose response in children with PIT (n=120) and CT (n=45) to test the hypotheses that participants with PIT have a diminished MPH response (amount of symptom change on the most effective dose) and derive less benefit from higher doses compared to those with CT. Since only one prior study has examined genetic predictors of MPH response within a PIT-only sample, our second specific aim (exploratory) is to determine the potential role of genetic polymorphisms (i.e., DRD4 and ADRA2A) on MPH response in children with PIT (n=120), examining both magnitude of symptom change and dose response curves . RELEVANCE: If subtype differences in stimulant response are identified, our findings may suggest more effective treatment strategies (i.e., different dosing guidelines) for children with ADHD-predominantly inattentive type (PIT). This study may also yield pharmacogenetic findings that, in the future, could enable doctors to tailor individual treatment plans for children with PIT, ameliorating the current practice of prescribing by trial and error.